Pyrazolo [4,3-d]pyrimidines

ABSTRACT

Pyrazolo[4,3-d]pyrimidines of the formula I                    
     and their physiologically acceptable salts, 
     in which 
     R 1 , R 2 , R 3 , R 4  and X have the meanings indicated in Claim  1 , exhibit phosphodiesterase V inhibition and can be employed for the treatment of disorders of the cardiovascular system and for the treatment and/or therapy of potency disorders.

The invention relates to compounds of the formula I

in which

R¹, R² in each case independently of one another are H, A, OH, OA orHal,

R¹ and R² together are also alkylene having 3-5 C atoms, —O—CH₂—CH₂—,—CH₂—O—CH₂—, —O—CH₂—O— or —O—CH₂—CH₂—O—,

R³, R⁴ in each case independently of one another are H or A,

X is R⁵, R⁶ or R⁷ monosubstituted by R⁸,

R⁵ is linear or branched alkylene having 1-10 C atoms, in which one ortwo CH₂ groups can be replaced by —CH═CH— groups, O, S or SO,

R⁶ is cycloalkyl or cycloalkylalkylene having 5-12 C atoms,

R⁷ is phenyl or phenylmethyl,

R⁸ is COOH, COOA, CONH₂, CONHA, CON(A)₂ or CN,

A is alkyl having 1 to 6 C atoms and

Hal is F, Cl, Br or I,

and their physiologically acceptable salts and solvates.

Pyrimidine derivatives are disclosed, for example, in EP 201 188 and WO93/06104.

The invention was based on the object of finding novel compounds havingvaluable properties, in particular those which can be used for theproduction of medicaments.

It has been found that the compounds of the formula I and their saltshave very valuable pharmacological properties together with goodtolerability.

In particular, they exhibit specific inhibition of cGMPphosphodiesterase (PDE V).

Quinazolines having cGMP phosphodiesterase-inhibiting activity aredescribed, for example, in J. Med. Chem. 36, 3765 (1993) and ibid. 37,2106 (1994).

The biological activity of the compounds of the formula I can bedetermined by methods such as are described, for example, in WO93/06104. The affinity of the compounds according to the invention forcGMP and cAMP phosphodiesterase is determined by the determination oftheir IC₅₀ values (concentration of the inhibitor which is needed inorder to achieve a 50% inhibition of the enzyme activity).

For carrying out the determinations, enzymes isolated according to knownmethods can be used (e.g. W. J. Thompson et al., Biochem. 1971, 10,311). For carrying out the experiments, a modified batch method of W. J.Thompson and M. M. Appleman (Biochem. 1979, 18, 5228) can be used.

The compounds are therefore suitable for the treatment of disorders ofthe cardiovascular system, in particular of cardiac insufficiency, andfor the treatment and/or therapy of potency disorders (erectiledysfunction).

The use of substituted pyrazolopyrimidinones for the treatment ofimpotence is described, for example, in WO 94/28902.

The compounds are efficacious as inhibitors of the phenylephrine-inducedcontractions in corpus cavernosum preparations from hares.

This biological action can be demonstrated, for example, according tothe method which is described by F. Holmquist et al. in J. Urol., 150,1310-1315 (1993). The inhibition of the contraction shows the efficacyof the compounds according to the invention for the therapy and/ortreatment of potency disorders.

The compounds of the formula I can be employed as pharmaceutical activecompounds in human and veterinary medicine. They can furthermore beemployed as intermediates for the preparation of further pharmaceuticalactive compounds.

The invention accordingly relates to the compounds of the formula I andto a process for the preparation of compounds of the formula I accordingto Claim 1 and their salts,

which is characterized in that

a) a compound of the formula II

in which

R³, R⁴ and X have the meanings indicated,

and L is Cl, Br, OH, SCH₃ or a reactive esterified OH group,

is reacted with a compound of the formula III

in which

R¹ and R² have the meanings indicated, or

b) in a compound of the formula I, a radical X is converted into anotherradical X by, for example, hydrolysing an ester group to a COOH group orconverting a COOH group into an amide or into a cyano group

and/or a compound of the formula I is converted into one of its salts.

Solvates of the compounds of the formula I are understood as meaningadducts of inert solvent molecules to the compounds of the formula Iwhich are formed on account of their mutual attractive force. Solvatesare, for example, mono- or dihydrates or alcoholates.

Above and below, the radicals R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, X and Lhave the meanings indicated in the formulae I, II and III, if notexpressly stated otherwise.

A is alkyl having 1-6 C atoms.

In the above formulae, alkyl is preferably unbranched and has 1, 2, 3,4, 5 or 6 C atoms and is preferably methyl, ethyl or propyl, furthermorepreferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but alson-pentyl, neopentyl, isopentyl or hexyl.

X is an R⁵, R⁶ or R⁷ radical monosubstituted by R⁷.

R⁵ is a linear or branched alkylene radical having 1-10 C atoms, wherethe alkylene radical is preferably, for example, methylene, ethylene,propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene,1-, 2- or 3-methylbutylene, 1,1-, 1,2- or 2,2-dimethylpropylene,1-ethylpropylene, hexylene, 1-, 2-, 3- or 4-methylpentylene, 1,1-, 1,2-,1,3-, 2,2-, 2,3- or 3,3-dimethylbutylene, 1- or 2-ethylbutylene,1-ethyl-1-methylpropylene, 1-ethyl-2-methylpropylene, 1,1,2- or1,2,2-trimethylpropylene, linear or branched heptylene, octylene,nonylene or decylene. R⁵ is furthermore, for example, but-2-enylene orhex-3-enylene.

A CH₂ group in R⁵ can preferably be replaced by oxygen. Ethylene,propylene, butylene or CH₂—O—CH₂ is very particularly preferred.

R⁶ is cycloalkylalkylene having 5-12 C atoms, preferably, for example,cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene,cyclohexylpropylene or cyclohexylbutylene.

R⁶ is also cycloalkyl preferably having 5-7 C atoms.

Cycloalkyl is, for example, cyclopentyl, cyclohexyl or cycloheptyl.

Hal is preferably F, Cl or Br, but also I.

The radicals R¹ and R² can be identical or different and are preferablyin the 3 or 4 position of the phenyl ring. They are, for example, ineach case independently of one another, H, alkyl, OH, F, Cl, Br or I ortogether alkylene, such as, for example, propylene, butylene orpentylene, furthermore ethylenoxy, methylenedioxy or ethylenedioxy.Preferably, they are also in each case alkoxy, such as, for example,methoxy, ethoxy or propoxy.

The radical R⁸ is preferably, for example, COOH, COOA such as, forexample, COOCH₃ or COOC₂H₅, CONH₂, CON(CH₃)₂, CONHCH₃ or CN, but inparticular COOH or COOA.

It applies to the entire invention that all radicals which occur anumber of times can be identical or different, i.e. are independent ofone another.

Accordingly, the invention in particular relates to those compounds ofthe formula I in which at least one of the radicals mentioned has one ofthe preferred meanings indicated above. Some preferred groups ofcompounds can be expressed by the following subformulae Ia to If, whichcorrespond to the formula I and in which the radicals not designated ingreater detail have the meanings indicated in the formula I, but inwhich

in Ia X is R⁵ substituted by COOH, COOA, CONH₂, CONA₂, CONHA or CN, oris phenyl or phenylmethyl;

in Ib R¹ and R² together are alkylene having 3-5 C atoms, —O—CH₂—CH₂—,—O—CH₂—O— or —O—CH₂—CH₂—O—,

X is R⁵ substituted by COOH, COOA, CONH₂, CONA₂, CONHA or CN, or isphenyl or phenylmethyl;

in Ic R¹, R² in each case independently of one another are H, A, OH, OAor Hal,

R¹ and R² together are also alkylene having 3-5 C atoms, —O—CH₂—CH₂—,—O—CH₂—O— or —O—CH₂—CH₂—O—,

X is R⁵ substituted by COOH, COOA, CONH₂, CONA₂, CONHA or CN, or isphenyl or phenylmethyl;

in Id R¹, R² in each case independently of one another are H, A, OH, OAor Hal,

R¹ and R² together are also alkylene having 3-5 C atoms, —O—CH₂—CH₂—,—O—CH₂—O— or —O—CH₂—CH₂—O—,

X is alkylene having 2-5 C atoms, which is monosubstituted by R⁸, orcyclohexyl, phenyl or phenylmethyl,

R³ is alkyl having 1-6 C atoms,

R⁴ is alkyl having 1-6 C atoms,

R⁸ is COOH or COOA,

A is alkyl having 1 to 6 C atoms,

Hal is F, Cl, Br or I;

in Ie R¹, R² in each case independently of one another are H, A, OH, OAor Hal,

R¹ and R² together are also alkylene having 3-5 C atoms, —O—CH₂—CH₂—,—O—CH₂—O— or —O—CH₂—CH₂—O—,

R³ is alkyl having 1-6 C atoms,

R⁴ is alkyl having 1-6 C atoms,

X is —(CH₂)₂₋₅—R⁸, 4-R⁸-cyclohexyl, 4-R⁸-phenyl or 4-(R⁸-methyl)phenyl;

in If R¹, R² in each case independently of one another are H, A, OH, OAor Hal,

R¹ and R² together are also alkylene having 3-5 C atoms, —O—CH₂—CH₂—,—O—CH₂—O— or —O—CH₂—CH₂—O—,

R³ is alkyl having 1-6 C atoms,

R⁴ is alkyl having 1-6 C atoms,

X is —(CH₂)₂₋₅—R⁸, in which one CH₂ group can be replaced by O, or is4-R⁸-cyclohexyl, 4-R⁸-phenyl or 4-(R⁸-methyl)phenyl,

R⁸ is COOH or COOA.

The compounds of the formula I and also the starting substances fortheir preparation are otherwise prepared by methods known per se, suchas are described in the literature (e.g. in the standard works such asHouben-Weyl, Methoden der organischen Chemie [Methods of organicchemistry], Georg-Thieme-Verlag, Stuttgart), namely under reactionconditions which are known and suitable for the reactions mentioned. Inthis case, use can also be made of variants which are known per se, butnot mentioned here in greater detail.

In the compounds of the formula II or III, R¹, R², R³, R⁴ and X have themeanings indicated, in particular the preferred meanings indicated.

If L is a reactive esterified OH group, this is preferablyalkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy) orarylsulfonyloxy having 6-10 C atoms (preferably phenyl- orp-tolylsulfonyloxy, furthermore also 2-naphthalenesulfonyloxy).

The compounds of the formula I can preferably be obtained by reactingcompounds of the formula II with compounds of the formula III.

If desired, the starting substances can also be formed in situ, suchthat they are not isolated from the reaction mixture but immediatelyreacted further to give the compounds of the formula I.

On the other hand, it is possible to carry out the reaction stepwise.

As a rule, the starting compounds of the formulae II and III are known.If they are not known, they can be prepared by methods known per se.

Compounds of the formula II can be prepared according to methods knownfrom the literature, e.g. from 4-amino-3-alkoxycarbonylpyrazoles bycyclization with nitriles and subsequent reaction of the cyclizationproducts with phosphorus oxychloride (analogous to Houben Weyl E9b/2).

In detail, the reaction of the compounds of the formula II with thecompounds of the formula III is carried out in the presence or absenceof an inert solvent at temperatures between approximately −20 andapproximately 150°, preferably between 20 and 100°.

The addition of an acid-binding agent, for example of an alkali metal oralkaline earth metal hydroxide, carbonate or bicarbonate or of anothersalt of a weak acid of the alkali metals or alkaline earth metals,preferably of potassium, sodium or calcium, or the addition of anorganic base such as triethylamine, dimethylamine, pyridine or quinolineor of an excess of the amine component can be favourable.

Suitable inert solvents are, for example, hydrocarbons such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbonssuch as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers such as ethylene glycol monomethyl or monoethyl ether(methyl glycol or ethyl glycol), ethylene glycol dimethyl ether(diglyme); ketones such as acetone or butanone; amides such asacetamide, dimethylacetamide, N-methylpyrrolidone or dimethylformamide(DMF); nitriles such as acetonitrile; sulfoxides such as dimethylsulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene;esters such as ethyl acetate or mixtures of the solvents mentioned.

It is furthermore possible to convert a radical X into another radical Xin a compound of the formula I, e.g, by hydrolysing an ester or a cyanogroup to a COOH group.

Ester groups can be hydrolysed, for example, using NaOH or KOH in water,water/THF or water/dioxane at temperatures between 0 and 100°.

Carboxylic acids can be converted, for example, using thionyl chlorideinto the corresponding carbonyl chlorides and these can be convertedinto carboxamides. Carbonitriles are obtained from these in a knownmanner by dehydration.

An acid of the formula I can be converted into the associated acidaddition salt using a base, for example by reaction of equivalentamounts of the acid and the base in an inert solvent such as ethanol andsubsequent evaporation. Suitable bases for this reaction are those whichyield physiologically acceptable salts.

Thus the acid of the formula I can be converted into the correspondingmetal salts, in particular alkali metal or alkaline earth metal salts,or into the corresponding ammonium salt, using a base (e.g. sodium orpotassium hydroxide or carbonate).

For this reaction, suitable organic bases are in particular also thosewhich yield physiologically acceptable salts, such as, for example,ethanolamine.

On the other hand, a base of the formula I can be converted into theassociated acid addition salt using an acid, for example by reaction ofequivalent amounts of the base and of the acid in an inert solvent suchas ethanol and subsequent evaporation. For this reaction, suitable acidsare in particular those which yield physiologically acceptable salts.Thus inorganic acids can be used, e.g. sulfuric acid, nitric acid,hydrohalic acids such as hydrochloric acid or hydrobromic acid,phosphoric acids such as orthophosphoric acid, sulfamic acid,furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic,sulfonic or sulfuric acids, e.g. formic acid, acetic acid, propionicacid, pivalic acid, diethylacetic acid, malonic acid, succinic acid,pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid,malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid,isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, naphthalene- mono- and -disulfonic acids andlaurylsulfuric acid.

Salts with physiologically unacceptable acids, e.g. picrates, can beused for the isolation and/or purification of the compounds of theformula I.

The invention furthermore relates to the use of the compounds of theformula I and/or their physiologically acceptable salts for theproduction of pharmaceutical preparations, in particular by anon-chemical route. In this case, they can be brought into a suitabledose form together with at least one solid, liquid and/or semi-liquidvehicle or excipient and, if appropriate, in combination with one ormore further active compounds.

The invention also relates to medicaments of the formula I and theirphysiologically acceptable salts as phosphodiesterase V inhibitors.

The invention furthermore relates to pharmaceutical preparationscomprising at least one compound of the formula I and/or one of itsphysiologically acceptable salts.

These preparations can be used as medicaments in human or veterinarymedicine. Possible vehicles are organic or inorganic substances whichare suitable for enteral (e.g. oral) or parenteral administration ortopical application and do not react with the novel compounds, forexample water, vegetable oils, benzyl alcohols, alkylene glycols,polyethylene glycols, glycerol triacetate, gelatin, carbohydrates suchas lactose or starch, magnesium stearate, talc and petroleum jelly. Inparticular, tablets, pills, coated tablets, capsules, powders, granules,syrups, juices or drops are used for oral administration, suppositoriesare used for rectal administration, solutions, preferably oily oraqueous solutions, furthermore suspensions, emulsions or implants, areused for parenteral administration and ointments, creams or powders areused for topical application. The novel compounds can also belyophilized and the lyophilizates obtained used, for example, for theproduction of injection preparations. The preparations indicated can besterilized and/or can contain excipients such as lubricants,preservatives, stabilizers and/or wetting agents, emulsifiers, salts foraffecting the osmotic pressure, buffer substances, colourants,flavourings and/or one or more further active compounds, e.g. one ormore vitamins.

The compounds of the formula I and their physiologically acceptablesalts can be used in the control of diseases in which an increase in thecGMP (cyclic guanosine monophosphate) level leads to inhibition orprevention of inflammation and muscle relaxation. The compoundsaccording to the invention can particularly be used in the treatment ofdiseases of the cardiovascular system and for the treatment and/ortherapy of potency disorders.

In this case, as a rule the substances are preferably administered indoses of between approximately 1 and 500 mg, in particular between 5 and100 mg, per dose unit. The daily dose is preferably betweenapproximately 0.02 and 10 mg/kg of body weight. The specific dose foreach patient depends, however, on all sorts of factors, for example onthe efficacy of the specific compound employed, on the age, body weight,general state of health, sex, on the diet, on the time and route ofadministration, on the excretion rate, pharmaceutical combination andseverity of the particular disorder to which the therapy applies. Oraladministration is preferred.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “customary working up”, means: if necessary, water is added,the mixture is adjusted, if necessary, depending on the constitution ofthe final product, to a pH of between 2 and 10 and extracted with ethylacetate or dichloromethane, the organic phase is separated off, driedover sodium sulfate and evaporated, and the residue is purified bychromatography on silica gel and/or by crystallization.

Mass spectrometry (MS): EI (electron impact ionization) M⁺ FAB (fastatom bombardment) (M+H)⁺.

EXAMPLE 1

3 g of methyl3-[7-chloro-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]propionateand 1.9 g of 3-chloro-4-methoxybenzylamine (“A”) in 50 ml ofdimethylformamide (DMF) are stirred at 60° for 12 hours in the presenceof potassium carbonate. After filtration, the solvent is removed and themixture is worked up in the customary manner. 4.6 g of methyl3-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]propionateare obtained as a colourless oil.

The following is obtained analogously by reaction of “A”.

with methyl2-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-yl]acetate

methyl2-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]acetate.

The following is analogously obtained by reaction of3,4-methylenedioxybenzylamine

with methyl3-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-yl]propionate

methyl3-[7-(3,4-methylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]propionate.

The following is analogously obtained by reaction of “A”.

with methyl4-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-yl]butyrate

methyl4-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]butyrate.

The following is analogously obtained by reaction of3,4-methylenedioxybenzylamine

with methyl4-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-yl]butyrate

methyl4-[7-(3,4-methylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]butyrate.

The following is analogously obtained by reaction of “A”.

with methyl5-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-yl]valerate

methyl5-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]valerate.

The following is analogously obtained by reaction of3,4-methylenedioxybenzylamine

with methyl5-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-yl]valerate

methyl5-[7-(3,4-methylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]valerate.

The following is analogously obtained by reaction of “A”.

with methyl7-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-yl]heptanoate

methyl7-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]heptanoate.

The following is analogously obtained by reaction of3,4-methylenedioxybenzylamine

with methyl7-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-yl]heptanoate

methyl7-[7-(3,4-methylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]heptanoate.

The following is analogously obtained by reaction of

with methyl2-[4-(7-chloro-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl-)cyclohex-1-yl]acetate

methyl2-{4-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]cyclohexyl-1-yl}acetate.

The following is analogously obtained by reaction of3,4-methylenedioxybenzylamine

with methyl2-[4-(7-chloro-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]cyclohex-1-yl]acetate

methyl2-(4-[7-(3,4-methylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]cyclohexyl-1-yl}acetate.

The following are analogously obtained by reaction of benzylamine

with methyl3-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-yl]propionate

methyl3-[7-benzylamino-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]propionate;

with methyl4-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-yl]butyrate

methyl4-[7-benzylamino-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]butyrate;

with methyl5-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-yl]valerate

methyl5-[7-benzylamino-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]valerate.

The following is analogously obtained by reaction of “A”.

with methyl4-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-yl]-cyclohexanecarboxylate

methyl4-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]cyclohexanecarboxylate

and the following is analogously obtained by reaction of3,4-methylenedioxybenzylamine

methyl4-[7-(3,4-methylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]cyclohexanecarboxylate.

EXAMPLE 2

4.3 g of methyl3-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-propionateare dissolved in 30 ml of tetrahydrofuran (THF) and, after addition of10 ml of 10% NaOH, stirred at 60° for 8 hours. After addition of 10%HCl, the deposited crystals are separated off and recrystallized frommethanol. 3.7 g of3-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]propionicacid, m.p. 178°, are obtained.

By evaporation with the equivalent amount of methanolic potassiumhydroxide solution, the potassium salt of the acid is obtained as anamorphous powder.

Analogously, from the esters mentioned in Example 1, the compounds

2-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]aceticacid,

3-[7-(3,4-methylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]propionicacid,

4-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]butyricacid, m.p. 152°;

4-[7-(3,4-methylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]butyricacid, m.p. 172°;

5-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]valericacid, m.p. 159°;

5-[7-(3,4-methylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]valericacid, ethanolamine salt, m.p. 160°;

7-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]heptanoicacid,

7-[7-(3,4-methylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]heptanoicacid,

2-{4-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]cyclohexyl-1-yl}aceticacid,

2-{4-[7-(3,4-methylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]cyclohexyl-1-yl}aceticacid,

3-[7-benzylamino-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-yl]propionicacid,

4-[7-benzylamino-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-yl]butyricacid,

5-[7-benzylamino-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-yl]valericacid, m.p. 185°;

4-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]cyclohexanecarboxylicacid,

4-[7-(3,4-methylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]cyclohexanecarboxylicacid,

are obtained.

Analogously, the compounds

5-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]valericacid, cyclohexylamine salt, m.p. 148°;

4-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-ethyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]butyricacid, m.p. 176°;

4-[7-(3,4-methylenedioxybenzylamino)-1-methyl-3-ethyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]butyricacid, m.p. 187°;

4-[7-(3-chloro-4-methoxybenzylamino)-1-ethyl-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]butyricacid, m.p. 206°;

4-[7-(3,4-methylenedioxybenzylamino)-1-ethyl-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]butyricacid, m.p. 177°;

4-[7-benzylamino-1-methyl-3-ethyl-1H-pyrazolo-[4,3-d]pyrimidin-5-yl]butyricacid, m.p. 208°;

4-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]butyricacid, m.p. 250°;

4-[7-(3,4-methylenedioxybenzylamino)-1-methyl-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]butyricacid, m.p. 225°;

4-[7-benzylamino-1-methyl-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]butyricacid, m.p. 201°;

5-[7-(4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]valericacid, m.p. 160°;

5-[7-(3-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]valericacid, m.p. 141°;

5-[7-(4-chlorobenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]valericacid, m.p. 148°;

5-[7-(3-chlorobenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]valericacid, m.p. 151°;

are obtained.

EXAMPLE 3

A mixture of 1.8 g of methyl4-[7-chloro-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]phenylcarboxylate(“B”) and 1.5 g of 3-chloro-4-methoxybenzylamine in 20 ml ofN-methylpyrrolidone is heated at 110° for 4 hours. After cooling, it isworked up in the customary manner. 2.2 g of methyl4-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-yl]benzoateare obtained.

Analogously to Example 2, from 1.2 g of the ester, 1.0 g of

4-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]benzoicacid, ethanolamine salt, m.p. 139°

is obtained.

Analogously to Example 1, from “B” and 3,4-methylenedioxybenzylamine

methyl4-[7-(3,4-methylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]benzoateand, therefrom, by ester hydrolysis

4-[7-(3,4-methylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]benzoicacid are obtained.

Analogously, the compounds

4-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]phenylaceticacid, glucamine salt, m.p. 114° and

4-[7-(3,4-methylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]phenylaceticacid

are obtained.

EXAMPLE 4

1 equivalent of3-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-propionicacid and 1.2 equivalents of thionyl chloride are stirred indichloromethane for 2 hours. The solvent is removed and3-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-propionylchloride is obtained. The product is transferred to aqueous ammonia,stirred for one hour and, after customary working up,3-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-yl]propionamideis obtained.

EXAMPLE 5

1 equivalent of DMF and 1 equivalent of oxalyl chloride are dissolved inacetonitrile at 0°. 1 equivalent of3-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]propionamideis then added. The mixture is stirred for one hour. After customaryworking up,3-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-yl]propionitrileis obtained.

EXAMPLE 6

Analogously to Examples 1, 2 and 3, by reaction of the correspondingchloropyrimidine derivatives with 3,4-ethylenedioxybenzylamine, thecarboxylic acids below are obtained

4-[7-(3,4-ethylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]butyricacid,

3-[7-(3,4-ethylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]propionicacid,

5-[7-(3,4-ethylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]valericacid,

7-[7-(3,4-ethylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]heptanoicacid,

2-{4-[7-(3,4-ethylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]cyclohexyl-1-yl}aceticacid,

4-[7-(3,4-ethylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]cyclohexanecarboxylicacid,

4-[7-(3,4-ethylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]benzoicacid,

4-[7-(3,4-ethylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]benzoicacid,

4-[7-(3,4-ethylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]phenylaceticacid.

Analogously, by reaction with 3,4-dichlorobenzylamine the compoundsbelow

4-[7-(3,4-dichlorobenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]butyricacid, m.p. 209°,

3-[7-(3,4-dichlorobenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]propionicacid,

5-[7-(3,4-dichlorobenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]valericacid,

7-[7-(3,4-dichlorobenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]heptanoicacid,

2-{4-[7-(3,4-dichlorobenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]cyclohexyl-1-yl}aceticacid,

4-[7-(3,4-dichlorobenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]cyclohexanecarboxylicacid,

4-[7-(3,4-dichlorobenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]benzoicacid,

4-[7-(3,4-dichlorobenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]phenylaceticacid,

are obtained.

Analogously, by reaction with 3-chloro-4-ethoxybenzylamine the compoundsbelow

4-[7-(3-chloro-4-ethoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]butyricacid,

3-[7-(3-chloro-4-ethoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]propionicacid,

5-[7-(3-chloro-4-ethoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]valericacid,

7-[7-(3-chloro-4-ethoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]heptanoicacid,

2-{4-[7-(3-chloro-4-ethoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]cyclohexyl-1-yl}aceticacid,

4-[7-(3-chloro-4-ethoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]cyclohexanecarboxylicacid,

4-[7-(3-chloro-4-ethoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]benzoicacid,

4-[7-(3-chloro-4-ethoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]phenylaceticacid,

are obtained.

Analogously, by reaction with 3-chloro-4-isopropoxybenzylamine thecompounds below

4-[7-(3-chloro-4-isopropoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]butyricacid,

3-[7-(3-chloro-4-isopropoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]propionicacid,

5-[7-(3-chloro-4-isopropoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]valericacid,

7-[7-(3-chloro-4-isopropoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]heptanoicacid,

2-{4-[7-(3-chloro-4-isopropoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]cyclohexyl-1-yl}aceticacid,

4-[7-(3-chloro-4-isopropoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]cyclohexanecarboxylicacid,

4-[7-(3-chloro-4-isopropoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]benzoicacid,

4-[7-(3-chloro-4-isopropoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]phenylaceticacid,

are obtained.

EXAMPLE 7

Analogously to Examples 1 and 2, the compound

[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]aceticacid, ethanolamine salt, m.p. 138°,

is obtained.

The following examples relate to pharmaceutical preparations:

Example A: Injection Vials

A solution of 100 g of an active compound of the formula I and 5 g ofdisodium hydrogenphosphate is adjusted to pH 6.5 in 3 l ofdouble-distilled water using 2 N hydrochloric acid, sterile filtered,dispensed into injection vials, lyophilized under sterile conditions andaseptically sealed. Each injection vial contains 5 mg of activecompound.

Example B: Suppositories

A mixture of 20 g of active compound of the formula I is fused with 100g of soya lecithin and 1400 g of cocoa butter, poured into moulds andallowed to cool. Each suppository contains 20 mg of active compound.

Example C: Solution

A solution is prepared from 1 g of an active compound of the formula I,9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of double-distilled water. It isadjusted to pH 6.8, made up to 1 and sterilized by irradiation. Thissolution can be used in the form of eye drops.

Example D: Ointment

500 mg of an active compound of the formula I are mixed with 99.5 g ofpetroleum jelly under aseptic conditions.

Example E: Tablets

A mixture of 1 kg of active compound of the formula I, 4 kg of lactose,1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearateis compressed in a customary manner to give tablets such that eachtablet contains 10 mg of active compound.

Example F: Coated Tablets

Analogously to Example E, tablets are pressed and are then coated in acustomary manner with a coating of sucrose, potato starch, talc,tragacanth and colourant.

Example G: Capsules

2 kg of active compound of the formula I are dispensed in a customarymanner into hard gelatin capsules such that each capsule contains 20 mgof the active compound.

Example H: Ampoules

A solution of 1 kg of active compound of the formula I in 60 l ofdouble-distilled water is sterile filtered, dispensed in ampoules,lyophilized under sterile conditions and aseptically sealed. Eachampoule contains 10 mg of active compound.

Example I: Inhalation Spray

14 g of active compound of the formula I are dissolved in 10 l ofisotonic NaCl solution and the solution is filled into commerciallyavailable spray containers having a pump mechanism. The solution can besprayed into the mouth or nose. One puff of spray (approximately 0.1 ml)corresponds to a dose of approximately 0.14 mg.

What is claimed is:
 1. A compound of the formula I

in which R¹ and R² are each, independently of one another, H, A, OH, OAor Hal, R¹ and R² together are alternatively alkylene having 3-5 carbonatoms, —O—CH₂—CH₂—, —CH₂—O—CH₂—, —O—CH₂—O— or —O—CH₂—CH₂—O—, R³ and R⁴are each, independently of one another, H or A, X is R⁵, R⁶ or R⁷monosubstituted by R⁸, R⁵ is linear or branched alkylene having 1-10carbon atoms, in which one or two CH₂ groups are optionally replaced by—CH═CH— groups, O, S or SO, R⁶ is cycloalkyl or cycloalkylalkylenehaving 5-12 carbon atoms, R⁷ is phenyl or phenylmethyl, R⁸ is COOH,COOA, CONH₂, CONHA, CON(A)₂ or CN, A is alkyl having from 1 to 6 carbonatoms, and Hal is F, Cl, Br or I, or a physiologically acceptable saltthereof.
 2. A compound of the formula I according to claim 1 that isselected from the group consisting of (a)5-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]pentanoicacid; (b)4-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]benzoicacid; (c)4-[7-(3,4-methylenedioxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]butyricacid; (d)5-[7-(benzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]pentanoicacid; (e)[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-]pyrimidin-5-ylmethoxy]aceticacid; and a physiologically acceptable salt thereof.
 3. A process forpreparing a compound of the formula I according to claim 1 or a saltthereof, comprising a) reacting a compound of the formula II

in which R³, R⁴ and X are as defined in claim 1, and L is Cl, Br, OH,SCH₃ or a reactive esterified OH group, with a compound of the formulaIII

in which R¹ and R² are as defined above, or b) converting a radical X ina compound of the formula I into another radical X by hydrolysing anester group to a COOH group or converting a COOH group into an amide orinto a cyano group and/or converting a compound of the formula I intoone of its salts.
 4. A pharmaceutical composition, comprising at leastone compound of the formula I according to claim 1 and/or aphysiologically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 5. A method of preparing a pharmaceuticalcomposition comprising bringing together a compound according to claim 1and a pharmaceutically acceptable carrier.
 6. A method of treating apotency disorder, comprising administering a compound of claim 1 to apatient in need thereof.
 7. A method of treating cardiac insufficiency,comprising administering a compound of claim 1 to a patient in needthereof.
 8. A method of treating erectile dysfunction, comprisingadministering a compound of claim 1 to a patient in need thereof.
 9. Acompound of the formula I according to claim 1, wherein X is R⁵monosubstituted by R⁸.
 10. A compound of the formula I according toclaim 1, wherein R¹ and R² together are alkylene having 3-5 C atoms,—O—CH₂—CH₂—, —O—CH₂—O— or —O—CH₂—CH₂—O—, and X is R⁵ substituted by R⁸.11. A compound of the formula I according to claim 1, wherein R¹, R², ineach case independently of one another, are H, A, OH, OA or Hal, or R¹and R² together are alkylene having 3-5 C atoms, —O—CH₂—CH₂—, —O—CH₂—O—or —O—CH₂—CH₂—O—, and X is R⁵ monosubstituted by R⁸.
 12. A compound ofthe formula I according to claim 1, wherein R¹, R², in each caseindependently of one another, are H, A, OH, OA or Hal, or R¹ and R²together are alkylene having 3-5 C atoms, —O—CH₂—CH₂—, —O—CH₂—O— or—O—CH₂—CH₂—O—, and X is alkylene having 2-5 C atoms, which ismonosubstituted by R⁸, R³ is alkyl having 1-6 C atoms, R⁴ is alkylhaving 1-6 C atoms, R⁸ is COOH or COOA, A is alkyl having 1 to 6 Catoms, and Hal is F, Cl, Br or I.
 13. A compound of the formula Iaccording to claim 1, wherein R¹, R², in each case independently of oneanother are H, A, OH, OA or Hal, or R¹ and R², together are alkylenehaving 3-5 C atoms, —O—CH₂—CH₂—, —O—CH₂—O— or —O—CH₂—CH₂—O—, R³ is alkylhaving 1-6 C atoms, R⁴ is alkyl having 1-6 C atoms, and X is—(CH₂)₂₋₅—R⁸, 4-R⁸-cyclohexyl, 4-R⁸-phenyl or 4-(R⁸-methyl)phenyl.
 14. Acompound of the formula I according to claim 1, wherein R¹, R², in eachcase independently of one another are H, A, OH, OA or Hal, R¹ and R²together are also alkylene having 3-5 C atoms, —O—CH₂—CH₂—, —O—CH₂—O— or—O—CH₂—CH₂—O—, R³ is alkyl having 1-6 C atoms, R⁴ is alkyl having 1-6 Catoms, X is —(CH₂)₂₋₅—R⁸, in which one CH₂ group is optionally replacedby O, or is 4-R⁸-cyclohexyl, 4-R⁸-phenyl or 4-(R⁸-methyl)phenyl, and R⁸is COOH or COOA.
 15. A compound of the formula I according to claim 1,wherein R⁵ is ethylene, propylene, butylene or CH₂—O—CH₂.
 16. A compoundof the formula I according to claim 1, wherein R⁸ COOH or COOA.